By Michael A. Thomas, MD, Professor, Reproductive Endocrinology and Infertility, Director, Reproductive Medicine Research, University of Cincinnati College of Medicine. Dr. Thomas reports no financial relationships relevant to this field of study.

Synopsis: Low levels of anti-Müllerian hormone in combination with an elevated day 2-3 follicle-stimulating hormone is associated with a high rate of aneuploid embryos.

In a prospective fashion, 372 patient were offered comprehensive chromosome screening because they fell into one or more of the following categories: advanced maternal age (≥ 39 years), history of two or more unsuccessful in vitro fertilization (IVF) cycles with adequate embryo quality, or unexplained recurrent pregnancy loss (two or more). All patients underwent testing for ovarian reserve by assessing serum anti-Müllerian hormone (AMH) at any time during the menstrual cycle and follicle-stimulating hormone (FSH) on cycle day 2 or 3. Also, early follicular estradiol, baseline transvaginal ultrasound for antral follicle count, and an endometrial cavity evaluation were performed. Normal values for AMH were defined as > 1 ng/mL and day 2-3 FSH as < 10 mIU/mL. The 279 subjects in group 1 had normal ovarian reserve testing as evidenced by normal values of both AMH and FSH. Group 2 consisted of 93 patients who had evidence of abnormal ovarian reserve testing with group A having a low AMH and elevated FSH (n = 25), group B demonstrating a normal AMH and elevated FSH (n = 34), and group C showing a low AMH and elevated FSH (n = 34). Patients underwent IVF and had their blastocysts biopsied, and 23 chromosomes were analyzed for potential abnormalities. Only euploid embryos were eventually transferred after being frozen by vitrification while awaiting biopsy results. When comparing group 1 (normal ovarian reserve testing) to group 2 (abnormal ovarian reserve testing), group 1 participants were younger (37.5 vs 38.8 yrs), had higher AMH (3.2 vs 1.3 ng/ml) and lower day 2-3 FSH concentrations (6.9 vs 10.5 mIU/mL), higher number of oocytes retrieved (20.8 vs 14.3), and a lower number of aneuploid blastocysts (14.3 vs 35.1). No difference in live birth rate was noted between group 1 or group 2 (58.4 vs 48.4%). Within group 2, the subjects in group A (lower AMH and high FSH) were noted to have a lower number of oocytes retrieved and a higher percentage of aneuploid blastocysts. No difference in live birth rate was noted within the group 2 subgroups. The authors concluded that women with biochemical evidence of diminished ovarian reserve have a higher percentage of aneuploid embryos. However, preimplantation genetic screening (PGS) allows the transfer of euploid embryos, which resulted in live birth rates that were equivalent regardless of their initial ovarian reserve testing.

Commentary

Ovarian reserve testing (antral follicle count, early follicular FSH, or AMH) is being used routinely by both reproductive endocrinologists and generalists to forecast a woman’s potential stimulation response to clomiphene citrate or gonadotropins, oocyte quality, and subsequent reproductive outcome. Despite poor numbers, some patients conceive. The study by Katz-Jaffe et al helps to demystify ovarian reserve testing as the last word in determining whether couples with a combined low AMH and high day 2-3 FSH should abandon all hopes of conceiving without the use of a donor oocyte.

In this study, PGS was available to those couples if the IVF cycle resulted in embryos that progressed to the blastocyst stage. One of the things that we don’t know from this study is how many of the couples with abnormal ovarian reserve testing started the study without going to the blastocyst stage. PGS has been used at IVF centers in patients with recurrent pregnancy losses, advanced maternal age, and those with a number of failed IVF cycles with or without good embryo quality. This current study suggests that, despite prediction of poor reproductive outcome and abnormal ovarian reserve on serum testing, outcomes may be good if PGS is performed. This provides an option to couples who have been routinely directed to donor egg. However, these data demonstrating a beneficial effect of PGS in poor prognostic groups are in contrast to other studies that have transferred euploid embryos with lower birth rates than reported here.1 In 2007, the Practice Committee of the American Society for Reproductive Medicine (ASRM) stated that they did not support the routine use of PGS to improve live birth rates in patients with recurrent pregnancy loss, previous implantation failure, or advanced maternal age.2

One major difference in the Shahine review and the ASRM document is use of fluorescence in situ hybridization or comparative genomic hybridization (CGH) in cleaved embryos, which allows analysis of selected numbers of chromosomes. In the Katz-Jaffe study, the trophectoderm of the blastocyst was biopsied and analyzed using metaphase CGH in subjects from 2007-2008 and single nucleotide polymorphism microarray in those participating from 2009-2011. These improved techniques allow analysis of all 23 chromosomes and therefore enhance accuracy in making a diagnosis of aneuploidy.

The results of the current study are promising for couples who have abnormal ovarian reserve testing despite age or poor outcomes in past ART cycles. However, these results need to be repeated in other centers using these same advanced techniques.

References

1. Shahine LK, Cedars MI. Fertil Steril 2006;85:51-56.

2. The Practice Committee of the Society for Assisted Reproductive Technology and the Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2007;88:1497-1504.